This invention is generally in the area of treatments of neural disorders and is in particular a method and composition for controlled drug delivery to neurological sites.
Problems with the nervous system due to injury, disease and congenital defects are widespread. The treatment of brain and spinal cord damage is one of the major goals in modern neurology. The causes for brain damage are many, including direct trauma due to physical insults, stroke as a result of hemorrhage or vascular occlusion, neuronal degeneration due to inherited metabolic and neurochemical dysfunction, and aging.
Unfortunately, few effective treatments currently exist. There are a number of approaches to treatment of the behavioral problems resulting from brain lesions. One option utilizes the brain's own capacity for restoration. For example, when additional transmitter precursor is made available to the neurons, there is an increase in transmitter synthesis by the brain.
The most successful form of treatment presently available for Parkinson's disease takes advantage of this principle. The behavioral symptoms, which are containing neurons, can be reduced by systemic application of L-dopa, a biosynthetic precursor of dopamine. The efficacy of therapy with L-dopa is due to its ability to pass the blood-brain-barrier, unlike dopamine. The blood-brain-barrier normally prevents most molecules from passing from the circulatory system into the brain.
Although L-dopa therapy is very effective in many cases, there are several problems associated with this therapy. There is a subset of patients, including those patients in advanced stages of the disorder, which are refractory or poorly responsive to L-dopa therapy. Furthermore, the "once-a-day" (or several times a day) treatment with L-dopa which results in pulsed rather than constant drug levels, in combination with the variation between patients with respect to drug absorption patterns, causes phasic swings of the symptom reduction and the patient's mood state during the course of the day.
The surprising lack of effective treatment for most nervous system injury has resulted in a search for novel approaches to the problem of manipulating brain damage. Two recently explored techniques are the use of tissue transplants into damaged brain, and peripheral or central injections of compounds which are believed to enhance regeneration or outgrowth of neural tissue.
Two types of tissue have been transplanted: fetal tissue and adrenal medullary tissue. The fetal brain transplants are based on experimental results showing that implantation of developing nerve tissue obtained from rat fetus and implanted into brain-damaged host animals reduces behavioral deficiencies due to the lesions. Some preliminary trials implanting adrenal medullary tissue into the brain were recently performed in human patients with Parkinson's disease in Sweden, Mexico, and, as of April 1987, the United States. The result was a reduction of some behavioral abnormalities. Anatomical studies currently underway to determine the physiological basis of the behavioral effects indicate that transplants do not function by establishing appropriate new axonal connections with the host tissue, but rather by the non-specific release of neurotransmitters ("trickling") and/or release of neurotrophic substances that promote neurite outgrowth, which may improve survival of, and possibly regenerate, partly damaged neurons.
From an ethical point of view it is difficult to conceive how human fetal tissue can be used clinically. The use of adrenal tissue also presents several problems, including the fact that the adrenal gland preferentially releases epinephrine (a metabolite of dopamine) rather than dopamine itself. In any case, if the non-specific release of transmitter and/or neurotrophic factors is the underlying mechanism of fetal or other tissue implants, and these factors can be identified and isolated or manufactured, it would be more reasonable to apply these substances directly to the brain in a controlled, sustained manner.
Neurotrophic substances play a number of potential therapeutic roles in other neurological disorders. One of the mechanisms by which the brain repairs itself following brain damage is through the regeneration and sprouting of new neuronal connections. It has recently been shown that injections of growth promoting, neurotrophic substances enhance the rate and extent of regeneration in the brain and bring about an enhanced degree of behavioral recovery in brain damaged animals. For example, gangliosides, which are able to cross the blood brain barrier, have been demonstrated to be effective for treating brain damage and are being used for the treatment of peripheral nerve disorders in Europe. Intracerebral injections of Nerve Growth Factor (NGF), a protein, also reduces behavioral deficits. Unfortunately, with the exception of gangliosides, all neurotrophic substances discovered so far, including NGF and similar substances which may be able to retard cell death in the brain, are large molecular weight molecules unable to pass through the blood-brain-barrier.
The inability of large molecular weight molecules such as proteins to cross the blood brain barrier is also a major problem in the potential use of enzyme replacement therapies for the treatment of lysosomal storage diseases such as Tay Sachs and Gaucher's disease and for the recently discovered use of beta interferon to reduce the frequency and severity of multiple sclerosis attacks. The beta interferon was administered directly into the spinal column in the initial clinical trials. Due to a number of side effects and discomfort to the patients, it is desirable to have another method of administration.
Various slow release polymeric devies have been developed in recent years for the controlled delivery of drugs, foods and pesticides. Using these devices, drugs can be released at constant, predictable rates in the human body. In comparison to traditional drug delivery methods, such as pills or injections, slow release polymeric devices have some distinct advantages. For example, it is thereby possible to maintain constant drug levels in the blood. Slow release polymers also provide a means for localized drug administration. Most drugs taken orally or otherwise must migrate throughout the entire body to reach their site of action. This often requires a high systemic dose to achieve the necessary local dose. With controlled-release implants, a continuous local level of drug can be maintained without distribution to other tissue or organs, where it could cause harm. By eliminating the high initial drug levels associated with conventional dosage forms, and maintaining drug levels in a therapeutically desired range, one can minimize side effects. Controlled drug delivery also reduces the need for follow-up care since a single controlled release dose can last for long periods of time. Other advantages include the preservation of volatile medications and drugs that are rapidly metabolized by the body, which must otherwise be given in high quantities and multiple doses. Controlled-release systems can protect the drug from degradation and allow it to be continuously released in unaltered form. This is particularly important for substances that are very expensive.
Another problem alleviated by controlled release compositions is in the handling and administration of the drug by the patient. Patient compliance is often difficult to achieve, particularly with a neurological disease such as Parkinson's disease, where depression and intellectual deterioration are common.
For these reasons, it is desirable to provide a controlled drug release system for use in treating nervous system disorders. Despite the use of controlled drug delivery systems in the treatment of a variety of diseases, including malignancy, and metabolic defects such as diabetes, it has never been directly applied to the treatment of nonmalignant nervous disorders, including ischemic, metabolic, congenital or degenerative disorders, wherein the purpose is to replace lost function or prevent defective function. This is despite the fact that the technology for encapsulating bioactive compounds within a polymeric device has been known for a long time and people have suggested that such devices might be useful for treatment of nervous disorders.
There are a number of reasons why this technology has not been successfully reduced to practice, including the complexity of the nervous system, the difficulties in delivery of substances to the nervous system, especially the brain, and the differences in response of individual patients to drugs delivered locally at a constant rate and dosage rather than in discrete doses via the circulatory system. An example of a prior art polyanhydride drug delivery device is taught by U.S. Pat. No. 3,625,214 to Higuchi. This device consists of a spirally wound layer of biodegradable polymer overlaid with drug which is released as the polymer degrades. Although it is noted that a variety of configurations can be used to achieve a desired release pattern, there is no teaching of how to treat neural disorders where the goal is to replace or supplement the biological function of the cells, not just to introduce a substance having a particular effect when administered by conventional means.
The nervous system is complex and physically different from the rest of the body. There are two "systems", the central nervous system and the peripheral nervous system. As used in the present invention, "nervous system" includes both the central (brain and spinal cord) and peripheral (nerves, ganglia, and plexus) nervous systems. The peripheral nervous system is divided into the autonomic and somatic nerves. The somatic nerves innervate the skeletal muscles and the autonomic nerves supply the innervation to the heart, blood vessels, glands, other visceral organs, and smooth muscles. The motor nerves to the skeletal muscles are myelinated, whereas the postganglionic autonomic nerves are generally nonmyelinated. The autonomic nervous system is further divided into the sympathetic and the parasympathetic nerves. In general, the sympathetic and parasympathetic systems are viewed as physiological antagonists. However, the activities of the two on specific structures may be different and independent or integrated and interdependent.
As is readily apparent, both the physical differences and interrelatedness of these components of the nervous system must be taken into account in designing a drug delivery system. As stated in The Pharmacological Basis of Therapeutics, edited by Gilman et al, on page 10 (MacMillan Publishing Company, NY 1980)
"The distribution of drugs to the CNS from the blood stream is unique, mainly in that entry of drugs into the CNS extracellular space and cerebrospinal fluid is restricted . . . Endothelial cells of the brain capillaries differ from their counterparts in most tissues by the absence of intercellular pores and pinocytotic vesicles. Tight junctions predominate, and aqueous bulk flow is thus severely restricted . . . The drug molecules probably must traverse not only endothelial but also perivascular cell membranes before reaching neurons or other drug target cells in the CNS . . . In addition, organic ions are extruded from the cerebrospinal fluid into blood at the choroid plexus by transport processes similar to those in the renal tubule. Lipid-soluble substances leave the brain by diffusion through the capillaries and the blood-choroid plexus boundary. Drugs and endogenous metabolites, regardless of lipid solubility and molecular size, also exit with bulk flow of the cerebrospinal fluid through the arachnoid villi . . . The blood-brain barrier is adaptive in that exclusion of drugs and other foreign agents such as penicillin or dtubocurarine protects the CNS against severely toxic effects. However, the barrier is neither absolute nor invariable. Very large doses of penicillin may produce seizures; meningeal or encephalitic inflammation increases the local permeability."
There are other problems. The immune system does not function within the CNS in the same manner as it does in the tissues and corporeal systems. A representative example of the problems in treating nervous system disorders is in the treatment of bacterial meningitis with antibiotics. Very toxic and high concentrations of the drugs are required.
As a result of the complexity of the nervous system and the physical differences as compared to other body organs and tissues, it has not been possible to design a system for drug delivery to the nervous system that is safe and effective, particularly prior to actual implantation in vivo in a human patient followed by long term observation.
It is therefore an object of the present invention to provide a system for use in treating disorders of both the central nervous system and the peripheral nervous system.
It is another object of the present invention to provide a system which is safe and does not raise serious ethical considerations.
It is a further object of the present invention to provide a system for treatment of nervous system disorders which is economical, practical and decreases problems with patient compliance.
It is yet another object of the present invention to provide a predictable system for direct, sustained, and linear application of drugs to the nervous system which can be modified as necessary to accomodate variations between patients with respect to the treatment required.